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SWI/SNF 家族突变在晚期 NSCLC 中的作用：遗传特征及免疫检查点抑制剂的治疗意义。

SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.

机构信息

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou.

Shanghai OrigiMed Co., Ltd, Shanghai.

出版信息

ESMO Open. 2024 Jun;9(6):103472. doi: 10.1016/j.esmoop.2024.103472. Epub 2024 Jun 3.

DOI:10.1016/j.esmoop.2024.103472
PMID:38833972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11179082/
Abstract

BACKGROUND

SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined.

PATIENTS AND METHODS

We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts.

RESULTS

Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNF NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNF NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection.

CONCLUSIONS

This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNF and TP53 subgroups.

摘要

背景

SWItch/Sucrose NonFermentable（SWI/SNF）突变因其与不良预后相关而受到越来越多的关注。然而，中国非小细胞肺癌（NSCLC）中 SWI/SNF 家族突变的遗传图谱尚不清楚。此外，尚未确定最佳的治疗策略。

患者和方法

我们收集了来自中国多个中心的 2027 例肺肿瘤样本的测序数据，全面分析了中国 NSCLC 人群中 SWI/SNF 家族的基因组特征。同时，我们纳入了中山大学肿瘤防治中心的 519 例 NSCLC 患者，以研究免疫治疗对 SWI/SNF 突变患者的潜在影响，并确定有益的亚群。我们还在多个公开可用的队列中验证了我们的发现。

结果

大约 15%的中国肺癌患者存在 SWI/SNF 染色质重塑复合物的突变，这些突变与 EGFR 突变互斥。接受一线化疗免疫治疗的 SWI/SNF NSCLC 患者的生存结局优于单独接受化疗的患者（中位无进展生存期：8.70 与 6.93 个月；P=0.028）。这一发现也通过使用 POPLAR/OAK 队列进行外部验证得到了证实。SWI/SNF NSCLC 常表现为高肿瘤突变负荷，同时存在 TP53 或 STK11/KEAP 突变。进一步分析表明，TP53 和 STK11/KEAP1 突变可以作为分层因素，促进个性化免疫治疗和指导患者选择。

结论

本研究在理解 SWI/SNF 基因突变的遗传和免疫学特征方面迈出了一步。此外，我们的研究表明免疫治疗对 SWI/SNF 突变患者，尤其是 SWI/SNF 和 TP53 亚组，具有显著的优势。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7335/11179082/fa5d10e88405/figs8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7335/11179082/1bf0fd04ab73/gr3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7335/11179082/3ea3af57e239/figs1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7335/11179082/03f8fc80334a/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7335/11179082/338cab011d25/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7335/11179082/cb093dc69e6a/figs6.jpg
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